Gene regulation could be the key to a longer lifespan

The researchers found that long-lived organisms often show high expression of genes involved in DNA repair, RNA transport and cellular skeletal organization and low expression of genes involved in inflammation and energy consumption.

Researchers at the University of Rochester who are interested in the genetics of longevity propose new targets to combat aging and age-related disorders.

Mammals that age at very different rates were created by natural selection. Naked mole rats, for example, can live up to 41 years, 10 times longer than mice and other rodents of comparable size.

What causes a longer lifespan? According to a recent study by biologists at the University of Rochester, a crucial piece of the puzzle lies in the mechanisms that control gene expression.

Vera Gorbunova, Professor of Biology and Medicine Doris Johns Cherry, Andrei Seluanov, the publication’s first author, Jinlong Lu, a postdoctoral researcher in Gorbunova’s lab, and other researchers have looked at genes linked to longevity in a recent article published in Cellular metabolism.

Their findings indicated that two regulatory mechanisms governing gene expression, known as circadian networks and pluripotency, are crucial for longevity. The findings are important for understanding how longevity occurs as well as providing new targets for combating aging and age-related disorders.

Chart of long-lived vs. short-lived species

By comparing the gene expression patterns of 26 species with varying lifespans, University of Rochester biologists found that the characteristics of different genes were controlled by circadian or pluripotency networks. Credit: University of Rochester Illustration/Julia Joshpe

Compare longevity genes

With maximum lifespans ranging from two years (shrews) to 41 years (naked mole-rats), the researchers analyzed the gene expression patterns of 26 mammalian species. They discovered thousands of genes positively or negatively correlated with longevity and linked to a species’ maximum lifespan.

They found that long-lived species tend to have low expression of genes involved in energy metabolism and inflammation; and high expression of genes involved in[{” attribute=””>DNA repair,

Two pillars of longevity

When the researchers analyzed the mechanisms that regulate the expression of these genes, they found two major systems at play. The negative lifespan genes—those involved in energy metabolism and inflammation—are controlled by circadian networks. That is, their expression is limited to a particular time of day, which may help limit the overall expression of the genes in long-lived species.

This means we can exercise at least some control over the negative lifespan genes.

“To live longer, we have to maintain healthy sleep schedules and avoid exposure to light at night as it may increase the expression of the negative lifespan genes,” Gorbunova says.

On the other hand, positive lifespan genes—those involved in DNA repair, RNA transport, and microtubules—are controlled by what is called the pluripotency network. The pluripotency network is involved in reprogramming somatic cells—any cells that are not reproductive cells—into embryonic cells, which can more readily rejuvenate and regenerate, by repackaging DNA that becomes disorganized as we age.

“We discovered that evolution has activated the pluripotency network to achieve a longer lifespan,” Gorbunova says.

The pluripotency network and its relationship to positive lifespan genes is, therefore “an important finding for understanding how longevity evolves,” Seluanov says. “Furthermore, it can pave the way for new antiaging interventions that activate the key positive lifespan genes. We would expect that successful antiaging interventions would include increasing the expression of the positive lifespan genes and decreasing the expression of negative lifespan genes.”

Reference: “Comparative transcriptomics reveals circadian and pluripotency networks as two pillars of longevity regulation” by J. Yuyang Lu, Matthew Simon, Yang Zhao, Julia Ablaeva, Nancy Corson, Yongwook Choi, KayLene Y.H. Yamada, Nicholas J. Schork, Wendy R. Hood, Geoffrey E. Hill, Richard A. Miller, Andrei Seluanov and Vera Gorbunova, 16 May 2022, Cell Metabolism.
DOI: 10.1016/j.cmet.2022.04.011

The study was funded by the National Institute on Aging. 

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